The broad focus of the proposed research is to understand how the activation of a resident nonparenchymal liver cell, the lipocyte (also known as Ito or stellate cell) is regulated in hapatic fibrosis and cirrhosis. Studies during the recent funding period have defined the major components of lipocyte activation, which is the transition of lipocytes from resting, vitamin A-rich cells to proliferating, fibrogenic cells with reduced vitamin A content. Activation is common to all forms of fibrosing liver injury and reflects a discrete program of gene expression involving induction of cytokines and their receptors, extracellular matrix molecules, cytoskeletal components, and metalloproteinases. A novel cDNA termed 'Zf9', has been cloned by subtractive hybridization from rat lipocytes activated in vivo. Zf9's cDNA sequence predicts 3 zinc finger domains which are nearly identical to those of the well characterized transcription factor Sp1, but whose serine-rich 5' activation domain is unique. Zf9 is an immediate-early lipocyte gene which is rapidly induced in mechanistically distinct models of liver injury in vivo, and in culture models of activation, but is not detected in a kidney model of fibrosis. The hypothesis is the Zf9 is a lipocyte-specific transcriptional regulator which plays a central role in lipocyte activation and has the biologic properties of other zinc finger transcription proteins. The Specific Aims are to: 1) Determine the structure and biologic function of Zf9 by a) full length rat cDNA cloning and homology cloning of human Zf9; b) assessing DNA binding; cv) examining transcriptional activity; d) determining if it is phosphorylated; e) evaluating whether its expression confers an activated phenotype on quiescent lipocytes. 2) Establish whether Zf9 is lipocyte- and liver-specific and define its subcellular location. 3) Examine Zf9s regulatory activity for 2 genes (collagen alpha1 (I) and TGFbeta1) whose induction is central to hepatic fibrosis and 4) Identify transcriptional coactivating proteins that complex with Af9 in activated lipocytes. The experiments are a direct extension of previously funded studies exploring the features of lipocyte activation, and are immediately relevant to the pathogenesis of cirrhosis in patients with chronic liver injury and fibrosis. The findings could lead to new treatments for this debilitating and incurable condition.